title: Characterization of a stable, hypertensive rat model suitable for the consecutive evaluation of human renin inhibitors.
abstract: BACKGROUND
  The hypertensive double-transgenic (dTG) rat strain, expressing human renin and angiotensinogen, develops severe hypertension and organ damage and 50% of individuals die by 7 weeks of age. Here, we characterise a variation of this model in which animals present stable hypertension.
  
  
  METHODS
  The effect of renin-angiotensin system blockers on blood pressure was determined with adult dTG rats treated with enalapril from 3 to 12 weeks of age. Tissue expression levels of renin and angiotensinogen were determined in dTG rats and rhesus monkeys by quantitative PCR.
  
  
  RESULTS
  Upon withdrawal from enalapril, mean arterial pressure (MAP) rose to 160-180 mmHg, with 95% of the female dTG rats surviving for 6 to 12 months, In Sprague-Dawley (SD) rats and rhesus monkeys, renin mRNA was absent or weakly expressed in most tissues, except for the kidneys and adrenals. In dTG rats, human renin expression was high in many additional tissues. The expression of human angiotensinogen in dTG rats followed a similar tissue pattern to SD and rhesus monkey angiotensinogen. Oral dosing of aliskiren, enalapril or losartan provided a similar maximal reduction in MAP and duration of efficacy in telemetrised dTG rats.
  
  
  CONCLUSIONS
  Enalapril-pretreated dTG rats are suitable for long-term MAP monitoring and sequential evaluation of human renin inhibitors.
authors.affiliation: Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Canada.
authors.forename: René
authors.initials: R
authors.lastname: St-Jacques
authors.forename: Sylvie
authors.initials: S
authors.lastname: Toulmond
authors.forename: Anick
authors.initials: A
authors.lastname: Auger
authors.forename: Christoph
authors.initials: C
authors.lastname: Binkert
authors.forename: Wanda
authors.initials: W
authors.lastname: Cromlish
authors.forename: Walter
authors.initials: W
authors.lastname: Fischli
authors.forename: Jennifer
authors.initials: J
authors.lastname: Harris
authors.forename: Patrick
authors.initials: P
authors.lastname: Hess
authors.lastname: Jie Lan
authors.forename: Susana
authors.initials: S
authors.lastname: Liu
authors.forename: Denis
authors.initials: D
authors.lastname: Riendeau
authors.forename: Beat
authors.initials: B
authors.lastname: Steiner
authors.forename: M David
authors.initials: MD
authors.lastname: Percival
mesh_terms: D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004656:Enalapril / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D005650:Fumarates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D008253:Macaca mulatta; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012083:Renin / Q000097:blood / Q000235:genetics; D014018:Tissue Distribution / Q000187:drug effects; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000808:Angiotensinogen; D004656:Enalapril; D005650:Fumarates; D012333:RNA, Messenger; D012083:Renin; D000092502:Renin Inhibitors; C446481:aliskiren